DISSERTATION RESEARCH: Evolution of transcription factor specificity and cooperativity

这个项目将结合联合收割机进化遗传学和生物化学来剖析动物基因调控的基本系统是如何进化的。它将探索可以打开或关闭特定基因的特定控制分子是如何进化的。这将通过追踪关键控制分子及其相应基因结构的古代进化变化来完成。它将把蛋白质与DNA结合的实验室测试与分子进化的计算机分析结合起来。更广泛的影响包括培训一名研究生，将计算机和实验方法结合起来研究分子进化。通过软件靴子训练营和科学推广介绍会传播统计编程技术也将增加妇女在跨学科科学中的代表性，转录是任何基因表达的第一步，因此许多人认为是基因组调节的基本步骤。生物体基因的正确调节取决于数千种不同蛋白质（称为转录因子）与其各自基因的正确配对。了解新的控制配对如何在不丧失原始功能的情况下发生是复杂基因组调控的核心。 类固醇受体是生物学上重要的转录因子。它们也是研究转录控制的一个很好的模型系统，因为它们由两个相关但功能不同的组组成，它们与特定基因的结合方式不同。一个基团主要与DNA分子的大沟结合;另一个基团与DNA的大沟和小沟结合。为了了解这两个群体中DNA结合和识别的进化，本研究利用祖先序列重建，沿着功能性实验室测定。受体功能和进化的计算分析将与实验室蛋白质结合试验相结合，以探索DNA小沟的形状以及DNA序列在新特异性的进化中很重要的假设。拟议的实验将描绘遗传和物理机制，通过这些机制，不同的DNA识别模式在这组分子中多样化。

This project will combine evolutionary genetics and biochemistry to dissect how a fundamental system of gene regulation in animals has evolved. It will explore how specific control molecules that can turn particular genes on or off have evolved. This will be done by tracing the ancient evolutionary changes in the structure of critical control molecules and their corresponding genes. It will integrate laboratory tests of protein to DNA binding with computer analysis of molecular evolution. Broader impacts include training of a graduate student in the integration of computer and experimental approaches to molecular evolution. Dissemination of techniques in statistical programming through software boot camps and science outreach presentations will also increase the representation of women in inter-disciplinary science.Transcription is the first step in the expression of any gene and hence is thought by many to be the fundamental step in regulation of the genome. Proper regulation of an organism's genes depends on the correct pairing of thousands of different proteins, called transcription factors, with their respective genes. Understanding how new control pairing occurs without loss of original functions is central to regulation in complex genomes. Steroid receptors are biologically important transcription factors. They are also an excellent model system for the study of transcriptional control since they consist of two related but functionally divergent groups that differ in the way they bind to specific genes. One group predominantly binds to a major groove of the DNA molecule; the other group binds to both major and minor grooves of DNA. To understand the evolution of DNA binding and recognition in these two groups this research utilizes ancestral sequence reconstruction, along with functional laboratory assays. Computational analysis of receptor function and evolution will be combined with laboratory protein binding assays to explore the hypothesis that the shape of the DNA minor groove as well as the DNA sequence was important in the evolution of novel specificity. The proposed experiments will delineate the genetic and physical mechanisms by which different modes of DNA recognition diversified in this group of molecules.